title: Quantitative analysis of the structural requirements for blockade of the N-methyl-D-aspartate receptor at the phencyclidine binding site.
abstract: Blockade of the N-methyl-D-aspartate receptor by uncompetitive antagonists has implications for symptomatic and neuroprotective therapy of various neuropsychiatric diseases. Since the three-dimensional (3D) structure of this ion channel is unknown, the structural requirements for uncompetitive inhibition were investigated by application of a three-step strategy: At first, Ki values were measured for a number of structurally diverse compounds at the phencyclidine (PCP) binding site in postmortem human frontal cortex. Second, a pharmacophore model was developed for this set of molecules employing a mathematical method called graph theory. The resulting pharmacophore provided a very good explanation for the ability of structurally diverse compounds to bind to the same binding site. Using the experimental data and the pharmacophore as a basis for the third step, a three-dimensional quantitative structure-activity relationship (3D-QSAR) applying comparative molecular field analysis (CoMFA) was performed. The QSAR proved to be highly consistent and showed good predictiveness for several additional molecules. The results give a deeper insight into the structural requirements for effective NMDA receptor antagonism and offer the opportunity for improved drug design. The study represents the first quantitative 3D-QSAR model for NMDA receptor blockade, and it comprises structurally very different molecules. That the alignment for a highly consistent CoMFA is based on an automated 3D pharmacophore analysis has important methodological implications.
authors.affiliation: Physical and Theoretical Chemistry Laboratory, University of Oxford, United Kingdom. romano@bellatrix.pcl.ox.ac.uk
authors.forename: R T
authors.initials: RT
authors.lastname: Kroemer
authors.forename: E
authors.initials: E
authors.lastname: Koutsilieri
authors.forename: P
authors.initials: P
authors.lastname: Hecht
authors.forename: K R
authors.initials: KR
authors.lastname: Liedl
authors.forename: P
authors.initials: P
authors.lastname: Riederer
authors.forename: J
authors.initials: J
authors.lastname: Kornhuber
mesh_terms: D001665:Binding Sites; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D010622:Phencyclidine / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D010622:Phencyclidine